KR820000254B1 - Process for preparing methanobenzo(g)quinoline-3-carboxylate - Google Patents

Abstract

Title compds. (I; R1 = H, lower alkyl, lower alkenyl, halo-lower alkenyl, cycloalkyl; R2, R2', R2", R2"' = halogen, H, lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy nitro, amino; R3 = H, lower alkyl; R4 = H, lower alkyl, lower alkoxy-lower alkyl, hydroxy-lower alkyl; R5 = lower alkyl, lower alkylthio-lower alkyl, lower alkoxy; Alk = lower alkyl; R5" = R5"' = R5; X = halogen), useful as analgesics, were prepd. by the reaction of R"-CO-X and alkali metal salt obtained from alkali metal amide and Ib.

Description

Method for preparing metanobenzo (g) quinoline-3-carboxylate

The present invention is an intermediate of the preparation of 11 (eq)-(2-acylethyl) -2, 6-methano-3-benzazosin, useful as analgesic and analgesic antagonist, lower alkyl 3-acyl-octahydro-2,5-meta It relates to a method for producing nobenzo [g] quinoline-3-carboxylate.

U.S. Pat.Nos. 3,932,422 are useful as intermediates for the preparation of 1, 2, 3, 4, 5, 6-hexahydro-11 (eq)-(2-acylethyl) -2, 6-methano-3-benzazocin. -Acyl-1, 2, 3, 4, 4a, 5, 10, 10a-octahydro-2, 5-methano benzo [g] -quinoline. However, even under the best reaction conditions, the process yields significant amounts of 2-substituted-1, 2, 3, 4, 4a, 5, 10, 10a-octahydro-3, 5-ethenobenzo [g] -quinoline as by-products. Is produced to reduce the yield of the desired product 2, 6-methano-3-benzazosine.

The present invention relates to lower alkyl-1-R ₁ -3-R ₅ CO-4aα-R ₃ -5α-R ₄ -6-R "useful as intermediates for the preparation of hexahydro-2, 6-methano- ₃ -benzazosine. ₂ -8-R ' ₂ -9-R "' ₂ -1, 2, 3, 4, 4a, 5, 10, 10a-octahydro-2, 5-methanobenzo [g] quinoline-3-carboxylate It relates to a manufacturing method of. In particular, the present invention provides valuable intermediates having the following structure (I).

The compound of formula (I) is lower-alkyl-1-R ₁ -3-R ₅ CO-4aα-R ₃ -5α-R ₄ -6-R ₂ "-7-R ₂ -8-R ₂ '-9 -R "' ₂ -1, 2, 3, 4, 4a, 5, 10, 10a-octahydro-2, 5-methanobenzo [g] quinoline-3-carboxylate, 3- R _1-6 (eq) -R _4-7 -R ₂ "-8-R ₂ -9-R ₂ '-10-R ₂ "' -11 (ax) -R3-11 (eq) -CH ₂ CH ₂ COR ₅ -2, 6- meth furnace 3-benzamide azo useful in the manufacture of God.

In the above formulas (I), (II)

R ₁ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, halo-low alkenyl, cycloalkyl, cycloalkyl-lower alkyl, 2- or 3-furylmethyl, or 1-3 on unsubstituted carbon atoms of the ring; 2- or 3-furyl methyl substituted with 2 methyl groups, or phenyl-lower alkyl, or 1-2 halogens (including bromine, chlorine, fluorine), lower alkyl, hydroxy, lower alkanoyloxy, lower in phenyl ring Alkoxy, lower alkyl mercapto, trifluoromethyl, amino, lower alkanoyl amino or phenyl-lower alkyl substituted with one methylenedioxy attached to adjacent carbon; R ₂ , R ₂ ', R ₂ ", R ₂ "' are each hydrogen, or three of them are hydrogen and the fourth is halogen (including bromine, chlorine and fluorine), or lower alkyl, hydroxy lower alkanoyloxy , Lower alkoxy, lower alkyl mercaptote, lifluoromethyl, nitro, amino, lower alkanoylamino, lower alkoxy carbonylamino, phenyl, or two adjacent together are methylenedioxy; R ₃ is hydrogen or lower alkyl; R ₄ is hydrogen, lower alkyl, lower alkoxy-lower alkyl, hydroxy-lower alkyl, lower alkylthio-lower alkyl, lower alkyl-sulfinyl-lower alkyl, phenylthio-lower alkyl, phenyl-sulfinyl-lower alkyl- Lower alkenyl or halo-lower alkyl, or R ₃ and R ₄ together are divalent lower alkylene,-(CH ₂ ) n-, where n is 3 or 4 and R ₅ is lower alkyl, lower alkylthio- Lower alkyl, lower alkoxy-lower alkyl, lower alkoxy, cycloalkyl, cycloalkyl-lower alkyl, 2- or 3-furyl, 2- or 3-furyl- (CH ₂ ) m, where m is an integer of 2-4 Or 2- or 3-furyl or 2- or 3-furyl- (CH ₂ ) m, wherein unsubstituted ring carbon atoms are substituted with 1-3 methyl groups, or phenyl, phenyl- (CH ₂ ) m or phenyl rings. Halogen (including bromine, chlorine, fluorine) lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, lower alkyl mercapto, trifluoromethyl, amino, lower alkanoylamino or adjacent Phenyl or phenyl- (CH ₂ ) m substituted with 1-2 groups of methylenedioxy to one carbon atom; AIK stands for lower alkyl.

As used herein, the term lower alkyl or lower alkoxy refers to a straight or branched chain saturated acyclic phase having from 1 to about 7 carbon atoms, for example methyl, ethyl, propyl, isopropyl butyl, non-adjacent t -Butyl, methoxy, ethoxy, propoxy, isopropoxy or t-butoxy.

The terms lower alkenyl, halo-lower alkenyl and lower alkynyl here refer to one atomic group of 3-7 carbon atoms having one double or triple bond, e.g. 1-propenyl, 2- Butenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-methyl-2-propenyl, 2-methyl, 2-propynyl, 2-propynyl, 2-butynyl, 4-pentynyl, 2-hexynyl, etc. and halo-lower alkynyl include 3-chloro-2-propenyl, 3-bromo-2-propenyl, 3, 3-dichloro-2-propenyl, 3-bromo-2-methyl -2-propenyl and the like.

The term cycloalkyl here means a saturated carbocyclic group having 3-7 carbon atom rings, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-methylcyclobutyl, 4-ethyl cyclohexyl, etc. .

Lower alkanoyl is a saturated aliphatic, monovalent carboxylic acid group having 1-4 carbon atoms, for example, formyl, acetyl, propionyl, butyryl, isobutyryl and the like.

The US patent _{1-R 1 -3-R 5} 'CO-4aα-R 3 -5α-R 4 -6-R 2 "-7-R 2 -8-R 2' in the following formula (Ia) - 9-R "' ₂ -1, 2, 3, 4, 4a 5, 10, 10a-octahydro-2, 5-methanobenzo [g] quinoline in an inert organic solvent or formic acid or benzyl-di-lower- A method for preparing a compound of formula (II) by heating with alkyl ammonium formate or tri-lower-alkylammonium formate is described. The target compound of formula (IIa) is prepared by breaking the compound of formula (Ia), which is a starting material, at the portion indicated by (b) to ring-open. However, in this method, since the portion represented by (a) is disconnected and then the R ' ₅ CO carbonyl group is cyclized to the nitrogen atom again, a considerable amount of 1-R _1-2 -R ₅ ' -4aα-R ₃ of formula (III) is used. -5α-R ₄ -6-R ₂ "-7-R ₂ -8-R ₂ '-1, 2, 3, 4, 4a 5, 10, 10a-octahydro-3, 5-ethenobenzo [g Quinoline is prepared to reduce the yield of the main product, Structural Formula (IIa).

Two equations are shown below.

Wherein R ₁ , R ₂ , R ′ ₂ , R ″ ₂ , R ₃ and R ₄ are as described above and R ₅ ′ is hydrogen, lower alkyl, phenyl or phenyl-lower-alkyl.

The compound of formula (II) may be prepared by incorporating the novel β-ketoester of formula (I) with formic acid or benzyl-di-lower-alkyl ammonium formate or tri-lower alkyl ammonium formate in an inert organic solvent such as 120-150 ° C. Heating at a temperature of does not produce by-products of the compound of formula IIl and can be prepared in high yield. The reaction is ring-opened between the carbon atoms of the 2- and 3- rings of the compound of formula (I), and ends immediately after the 3-carbo lower alkoxy group, COOAIK, is decarboxylated. Suitable solvents are toluene, xylene, mesitylene. A particularly good solvent is formic acid in mesitylene and a particularly good method is ring opening in trimethyl ammonium formate.

In particular, the compound of formula (II) wherein optionally one of R ₂ , R ₂ ′, R ₂ ″ and R ₂ ″ is hydroxy has the ether group from the corresponding ether whose corresponding group is lower alkoxy, an aqueous solution or sodium profile of hydrobromic acid Prepared by decomposition with sulfides. When using an aqueous hydrobromic acid solution for decomposition, the ether solution is refluxed in the aqueous hydrobromic acid solution and separated directly from the reaction mixture in the form of hydrobromide or in neutral solution as a free base.

When sodium propyl sulfide is used, it is carried out by refluxing the ether solution in an inert organic solvent such as dimethylformamide with an excess of sodium propyl sulfide prepared by adding propanethiol to sodium hydride.

The advantage of using the structural formula (I) β-ketoester over the structural formula (Ia) is that the reaction time of the former takes several days and sometimes 6 days, but the reaction using the β-ketoester of structural formula (I) The reaction is completed in 4-6 hours when using formic acid dissolved in mesitylene as a solvent in most cases after several minutes to several hours, and in 9-13 minutes using trimethylammonium formate at 145 ° C. . In all cases, samples of the reaction mixture are regularly placed on a thin layer chromatography plate as the reaction proceeds and the starting material disappears as the reaction time elapses.

The compound of formula (I) is represented by 1-R ₁ --3-R ₅ "CO-4aα-R ₃ -5α-R ₄ -6-R ₂ " -7-R ₂ -8-R ₂ '-of formula (Ib). 9-R "' ₂ -1, 2, 3, 4, 4a 5, 10, 10a-octahydro-2, 5-methanobenzo [g] quinoline in an inert organic solvent such as sodium amide or lithium diiso The reaction is carried out with an alkali metal amide such as propyl amide and the resulting alkali metal salt is reacted with a suitable acyl halide R ₅ "'-CO-X or lower alkyl haloformate according to the following reaction sequence.

Wherein _{R 1, R 2, R '} 2, R 2 ", R 2"', R 3, R 4 and AIK is the same as the above R _"5 and R _5" 'is R ₅ "is not a lower alkoxy Is the same as R ₅ except that R ₅ "'represents lower alkoxy, X is halogen and MN = B is an alkali metal (M) amide (N = B). The reaction is well performed at -10 ° C to -70 ° C.

Suitable solvents are tetrahydrofuran, diethyl ether or dioxane. Structural (Ib) compounds as starting materials and methods for their preparation are known from US Pat. No. 3,932,422.

As mentioned above, the 3-acyl group (COR ₅ ″) in the formula (Ib) compound and the 3-acyl (R ₅ CO) and 3-carbo-lower alkoxy group (COOAIK) in the formula (I) β-ketoester The steric structure is not clear, but as far as 2, 6-methano-3-benzazosine of formula (II) (prepared from β-ketoester of formula (I)) 3 of the compound of formula (I) The question of the steric structure at the position is debatable, because the compound of formula (I) is destroyed at position 3 and is converted to the compound of structure (II). All of the compounds having the structural formula (I) are used in the preparation of the structural formula (II) compounds.

Acylation or carboxylation of the compound of formula (Ib) immediately after ring opening and decarboxylation results in one clean compound of formula (II).

The compounds of the present invention may exist in structural isomers, ie optical isomers and geometric isomers. If desired, the separation or production of a particular structural chemical form can be carried out according to known methods known in the art. In naming compounds of formula II, "ax" means axial, "eq" means equi-orial, and the structure is drawn with reference to an aromatic ring. The 6 (eq) and 11 (ax) compounds of II) are cis structures and the 6 (eq) and 11 (eq) compounds are trans structures.

In the nomenclature of the compounds of formulas (I), (Ia), (Ib), (Ic), and (III), the structure follows the nomenclature of the aromatic hydrogen ring, and the "β" designation is 2, 5- of the compound of formula It shows cis structure in the 3, 5-etheno linkage of a metano linkage or a structural formula (III) compound. In contrast, the symbol "α" indicates trans structure in the same group.

The structure of the compound of the present invention was determined by synthesis type or elemental analysis and infrared or nuclear magnetic resonance spectra.

Reaction progress or product identity was usually confirmed by thin layer chromatography.

The following describes methods and processes for carrying out the invention and the most advantageous methods of carrying out the invention to enable those skilled in the art to make and use the invention.

Unless otherwise noted, the melting point is not accurate.

A. Preparation of lower alkyl 3-R ₅ CO-octahydro-2,5-methano-benzo [g] quinoline-3-carboxylate of formula (I).

1. Process by acylation of the corresponding lower alkyl 3-carbosylate.

Example 1

A. 13.1 g (0.13 mole) of redissolved in 110 ml of anhydrous tetrahydrofuran in a solution of 50 ml (0.12 mole) of 2,4N n-butyltium in hexane over 0 minutes at 0 ° C. An amine solution was added.

The mixture was cooled to −60 ° C. and dissolved in 110 ml of tetrahydrofuran in 34.3 g (0.1 mol) of ethyl-7-methoxy-1, 4aα, 5α-trimethyl-1, 2, 3, 4, 4a, 5, 10, 10a-octahydro-2, 5-methanobenzo [g] quinoline-3-carboxylate solution was added for 2 hours. This solution was mixed with 18.8 g (0.13 mol) of redistilled hexanoyl chloride solution dissolved in 110 ml of tetrahydrofuran at -60 ° C. for about 30 minutes. The clear reaction mixture was added to 500 ml of sodium bicarbonate solution, extracted twice with 100 ml of ether, and the extract was washed once with brine, dried over sodium sulfate and evaporated to yield 44 g of oily substance which, when left to become a solid. The residue was recrystallized from hexane to give 27.5 g (63%) of ethyl-3- (1-oxohexyl) -7-methoxy-1, 4aα, 5α-trimethyl-1, 2, 3, 4, 4a, 5, 10, 10a-octahydro-2, 5-methanobenzo [g] quinoline-3-carboxylate is produced.

Melting point 117-120 ℃

In the same manner as above, the following structural formula (I) compound was also obtained.

B. ethyl 7-methoxy-1, 4aα, 5α-trimethyl-3- (4-methyl-1-oxo-pentyl) -1, 2, 2, 3, 4, 4a, 5, 10, 10a-octahydro -2,5-methanobenzo [g] quinoline-3-carboxylate (22.8 g, 43%, at 97-100 ° C. pentane) has 40.5 g (0.12 mol) of ethyl 7-methoxy-1,4aα, 5α-trimethyl-1, 2, 3, 4, 4a, 5, 10, 10a-octahydro-2, 5-romethanobenzo [g] quinoline-3-carboxylate with 0.13 mole of lithium diisopropyl amide The resulting salt was prepared by reacting with 17.5 g (0.13 mol) of 4-methylpentanoyl chloride.

C. Ethyl 7-methoxy-1, 5α-dimethyl-3- (1-oxopentyl) -1, 2, 3, 4, 4a, 5, 10, 10a-octahydro-2, 5-methanobenzo [ g] Quinoline-3-carboxylate (5.2 g, 27% melting point at 87-92 ° C. pentane) is 15.0 g (0.046 moles) of ethyl 7-methoxy-1, 5α-dimethyl-1, 2, 3, 4 , 4α, 5, 10, 10a-octahydro-2, 5-methanobenzo [g] quinoline-3-carboxylate was prepared by reacting with 0.047 mole of lithium diisopropylamide.

In a similar manner to Example 1 described above, the compound of formula (I) described in Table 1 was also prepared in a similar manner. In the section used for melting point and recrystallization, note the melting point (℃) / solvent.

TABLE 1

2. Method of carboxylation of the corresponding 3-carboxylate or 3-R " ₅ CO ketone

Example 2

A. A solution of 0.055 mole of lithium diisopropylamide in 60 ml of tetrahydrofuran was prepared from butylrium and diisopropylamine according to the method described in Example 1 above. The resulting solution was cooled to -75 ° C. and maintained at a temperature of 17.1 g (0.05 mol) of ethyl 7-methoxy-1,4aα, 5α-trimethyl-1, 2, 3, 4, 4a, 5, 10 And 10a-octahydro-2 and 5-methanobenzo [g] quinoline-3-carboxylate over about 30 minutes. To this solution was added 5.4 g (0.05 mol) of ethyl chloroformate solution dissolved in 80 ml of tetrahydrofuran for 1 hour at -75 ° C, the mixture was cooled for 1 hour and then poured into 400 ml of sodium bicarbonate solution and in Example 1 Completion of the reaction in the same manner yields 9.7 g of impure target product, and recrystallization with pentane results in 6.3 g (30%) of diethyl-7-methoxy-1, 4aα, 5α-trimethyl-1, 2, 3, 4 , 4a, 5, 10a-octahydro-2, 5-methanobenzo [g] quinoline-3, 3-dicarboxylate was obtained. Melting point 89-91 ℃

A similar 3-R " ₅ CO-1, 2, 3, 4, 4a, 5, 10, 10a-octahydro-2, 5-methanobenzo [g] quinoline and ethyl chloro of the formula (Ib) The compound of formula (I) as shown in Table 2 is likewise prepared by acting formate in the presence of diisopropylamide.

TABLE 2

Claims (1)

The following compound of formula (Ib) is reacted with an alkali metal amide and the resulting alkali metal salt is reacted with a compound of formula R ₅ "-CO-X to give the metanobenzo [g] quinoline-3-carboxylate compound of formula (I) How to manufacture.

In the above formula R ₁ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, halo-low alkenyl, cycloalkyl, cycloalkyl lower alkyl, 2- or 3-furylmethyl, or 1-3 carbon atoms in unsubstituted ring Halogen, lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, lower alkyl mercapto, trifluoromethyl, amino, lower alka to 2- or 3-furylmethyl or phenyl-lower alkyl or phenyl rings substituted with methyl groups A phenyl-lower alkyl group substituted with 1-2 of one methylene dioxy attached to a noylamino or adjacent carbon atom, and R ₂ , R ' ₂ , R ₂ "and R ₂ "' are all hydrogen or three of them Is hydrogen and the other is halogen, lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, lower alkyl mercapto, trifluoromethyl, nitro, amino, lower alkanoylamino, lower alkoxycarbonylamino, phenyl or Two adjacent together methylenedi And when; R ₃ is hydrogen or lower alkyl; R ₄ is hydrogen, lower alkyl, lower alkoxy-lower alkyl, hydroxy lower alkyl, lower alkylthio-lower alkyl, lower alkyl, sulfinyl-lower alkyl, phenylthio-lower alkyl, phenyl-sulfinyl-lower alkyl, lower Alkenyl or haloloweralkyl, or R ₃ and R ₄ together are divalent loweralkylene- (CH ₂ ) n—, where n is an integer of 3 or 4; R ₅ is lower alkyl, lower alkylthio-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy, cycloalkyl, cycloalkyl-lower alkyl, 2- or 3-furyl, 2- or 3-furyl- (CH ₂ ) m (Where m is an integer of 2-4), or unsubstituted, 2- or 3-pril or 2- or 3-furyl- (CH ₂ ) m, or phenyl, in which a substituted carbon atom is substituted with 1-3 methyl groups Phenyl- (CH ₂ ) m or a phenyl ring attached to halogen, lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, lower alkyl mercapto, trifluoromethyl, amino, lower alkanoylamino or adjacent carbon atoms Phenyl substituted with 1-2 of one methylenedioxy group or phenyl- (CH ₂ ) m; Alk is lower alkyl; R _"5 and R"_'5 and R ₅ are the same (however, "time is not a lower alkoxy R _5' R ₅ 'is to be a lower alkoxy group); X is halogen.